The abrupt loss of the sense of hearing is both frightening and alienating, but in some cases is reversible. The last ten years have seen the beginning of clinical treatment of hearing loss with systemic administration of immunosuppressive agents such as dexamethasone and prednisone. This course of treatment was tried because of the introduction of the idea that the inner ear is vulnerable to immune reactions and more importantly, that these immune reactions cause hearing losses. The fact that patients derive relief from their symptoms provides the motivation to both identify patients who may be helped by this treatment and to obtain the maximum understanding of immune mechanisms within the inner ear tissues. The development of an inner ear immune response involves the endolymphatic sac, an extension of the membraneous labyrinth within the temporal bone projecting into the dura adjacent to the sigmoid sinus of the posterior cranial fossa. The experimental, surgical destruction of the endolymphatic sac results in an attenuated immune response within the inner ear in response to an immunologic challenge. In normally housed laboratory animals and in the human endolymphatic sac reside the only immunocompetent cells found within the inner ear. Antigens introduced in the cochlear fluids very rapidly diffuse into the perisaccular connective tissue and subsequently are found within macrophages in the luminal space of the sac. For these reasons it is hypothesized that the endolymphatic sac is instrumental in connecting the inner ear to the systemic immune system and that signals generated here are used to initiate, modulate and resolve immune responses in the inner ear. The intent of the proposed experiments is to test this hypothesis and thereby gain an understanding of the initial events in the immune response. Such knowledge will enable clinicians to improve the treatments administered to patients who experience the unfortunate and potentially devastating trauma of rapidly progressing sensorineural hearing loss.